The role of Plk4/Sak in cell cycle regulation and cancer
By: by Michael Augustine Ko.
Published: 2006
Language: eng
Number of pages: 239
ISBN-13: 9780494158777
Description: Plk4, formerly known as Sak, is a member of the polo-like family of kinases (Plks). In recent years, the Plks have emerged as critical regulators of cellular division. Plk4, the most divergent member of the Plks, is essential for cell cycle progression in metazoans (Hudson et al., 2001). Cell cycle regulatory proteins are commonly dosage dependent and therefore, mice and cells carrying one copy of a targeted deletion of Plk4 (termed Plk4+/-) are examined to determine the requirement for adequate Plk4+/-) to maintain replicative fidelity. Elderly Plk4+/- mice spontaneously develop primary cancers of the liver and lung at much higher rates that wild type littermates. Plk4+/- murine embryonic fibroblasts (MEFs) exhibit cytokinesis failure, and increased polyploidy in vitro. Plk4+/- MEFs display insufficient activation of RhoA in telophase, a critical mediator of cleavage furrow localization. Cytokinesis failure leads to centrosomal amplification, errors in spindle formation and DNA segregation, observed at a 5 fold greater frequency in Plk4+/- compared with Plk4+/+ MEFs. In a partial hepatectomy (PH) model of liver regeneration, Plk4+/- hepatocytes display a significant delay in cell cycle entry, with loss of p53 activation and loss of precise mitotic cyclin regulation. Plk4+/-) binds p53 and phosphorylates it at serine 392 in vitro, and Plk4+/-) MEFs are deficient in UV mediated apoptosis. Lastly, loss of Plk4+/-) in p53+/- mice accelerates tumorigenesis, indicating a role of Plk4+/-) in p53 mediated tumor suppression. Plk4 +/-) haploinsufficiency leads to a complex phenotype of chromosomal instability and carcinogenesis.
Notes: Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3593.

Thesis (Ph.D.)--University of Toronto, 2006.

Includes bibliographic references.

Electronic version licensed for access by U. of T. users.